PAS-004

PAS-004

Our lead drug candidate, PAS-004, is in clinical development for Neurofibromatosis Type 1 (NF1)-associated plexiform neurofibroma (PN) and advanced solid tumors.

PAS-004 is a small-molecule allosteric inhibitor of MEK 1/2, with potential across a range of RASopathies – including neurocutaneous manifestations of NF1, various MAPK pathway-driven tumors, ALS, and other indications.

PAS-004 has received the following FDA designations:

  • Orphan Drug Designation for NF1
  • Rare Pediatric Disease Designation for NF1
  • Fast Track Designation for NF1-associated plexiform causing significant morbidity
  • Orphan Drug Designation for Amyotrophic Lateral Sclerosis (ALS)

The Science

MEK 1 and MEK 2 are kinases in the MAPK pathway, which drives cell proliferation, differentiation, and survival.When this pathway is abnormally overactive, it can fuel tumors, fibrosis, and other diseases. MEK inhibitors work by blocking ERK activation, which can trigger cell death and slow tumor growth.

Current FDA-approved MEK inhibitors for NF1-PN have certain limitations: known toxicities and high rates of adverse events that can lead to dose interruptions, discontinuations, and/or poor tolerability.

PAS-004 is designed to address these issues through its macrocyclic structure, which we believe offers several advantages:

  • Improved selectivity and higher oral bioavailability
  • Better metabolic stability — structural rigidity enables stronger target binding
  • No primary alcohol or hydroxamate group, a known metabolic liability in earlier MEK inhibitors, while still preserving key protein/ligand contacts

This translates into a favorable pharmacokinetic profile: a long half-life, a low peak-to-trough (Cmax/Cmin) ratio, and stable steady-state drug levels. We believe sustained MAPK suppression could mean better efficacy, safety, and a broader therapeutic window than current FDA-approved MEK inhibitors for NF1-PN.

About Neurofibromatosis Type 1

NF1 is a RASopathy — one of a group of neurocutaneous disorders affecting the skin and central nervous system. It affects roughly 1 in 3,000 newborns worldwide, with about 115,000 patients in the U.S.

Genetic basis: NF1 results from mutations in the NF1 gene, which normally encodes the tumor suppressor neurofibromin. Losing neurofibromin function locks Ras in its active state, driving MEK and ERK activity.

Plexiform neurofibromas (PN):

  • Tumors arising from the nerve sheath, growing through and around nerves, sometimes across multiple branches
  • Occur in 30–50% of NF1 patients
  • Can undergo malignant transformation
  • Morbidity mainly comes from tumors compressing surrounding structures — potentially life-threatening near vital organs or upon malignant transformation

Cutaneous neurofibromas (CN):

  • A hallmark of NF1, occurring in over 95% of patients
  • Neoplasms of Schwann cells, appearing as soft dermal nodules anywhere on the body
  • Though benign, patients often consider CNs the most burdensome aspect of the disease
  • Can number in the hundreds to thousands, causing disfigurement
  • Linked to lower quality of life through embarrassment, disrupted daily activities, and social impact.